PET plays an increasing role in the management of breast cancer, especially in characterizing breast cancer and evaluating its response to treatment. However, the clinical use of PET in breast cancer has been largely restricted to locally advanced or metastatic disease due to the difficulty of accurately identifying and quantifying tracer uptake in smaller breast tumors. To overcome this limitation, other investigators have designed and tested dedicated devices to improve primary breast cancer detection;however these devices were not well suited, nor intended, for image quantification and generally were not able to use the PET information to direct biopsy, necessary to confirm tumor features identified by PET. To address the need for quantitative imaging and biopsy capability, and motivated by the desire to characterize smaller breast tumors and follow their response to therapy, we will build and implement a dedicated high-resolution breast positron emission tomograph (PET) device that attaches to a conventional mammography machine. PET images and digital mammograms will be acquired without moving the moderately compressed breast between image acquisitions. A key aspect of our proposed system is that it will be a true tomographic imaging PET device, rather than a positron emission mammographic (PEM) scanner. Thus the PET images will be quantitative, unlike PEM. The quantitative physiological information can be used to investigate biological heterogeneity of the tumor, uptake of molecular markers, and response to treatments. The proposed system will also accommodate a biopsy guidance mechanism that will allow a biopsy needle to be guided by the PET image, or the merged PET- mammogram image. This approach will provide quantitative imaging of smaller, earlier stage breast tumors, with biopsy direction, both necessary for our ongoing studies of breast cancer characterization and response to treatment. PUBLIC HEALTH RELEVANCE: This project aims to develop a scanner optimized for molecular breast imaging that complements mammography, is capable of biopsy needle guidance, and operates attached to a mammography machine. This scanner will greatly reduce the threshold of functional PET breast cancer imaging, from around 20 mm to around 5 mm, which will allow characterization earlier in the course of the disease giving more opportunity for the best treatment selection. This tool will assist in the complex characterization of breast malignancies that is proving to be an increasingly important task in patient prognosis as the multiplicity of breast cancer molecular pathways is uncovered.